Identification of a novel agonist of peroxisome proliferator-activated receptors alpha and gamma that may contribute to the anti-diabetic activity of guggulipid in Lep(ob)/Lep(ob) mice.
The ethyl acetate extract of the gum of the guggul tree, Commiphora mukul (guggulipid), is marketed for the treatment of dyslipidaemia and obesity. We have found that it protects Lep(ob)/Lep(ob) mice from diabetes and have investigated possible molecular mechanisms for its metabolic effects, in particular those due to a newly identified component, commipheric acid. Both guggulipid (EC(50)=0.82 microg/ml) and commipheric acid (EC(50)=0.26 microg/ml) activated human peroxisome proliferator-activated receptor alpha (PPARalpha) in COS-7 cells transiently transfected with the receptor and a reporter gene construct. Similarly, both guggulipid (EC(50)=2.3 microg/ml) and commipheric acid (EC(50)=0.3 microg/ml) activated PPARgamma and both promoted the differentiation of 3T3 L1 preadipocytes to adipocytes. Guggulipid (EC(50)=0.66 microg/ml), but not commipheric acid, activated liver X receptor alpha (LXRalpha). E- and Z-guggulsterones, which are largely responsible for guggulipid's hypocholesterolaemic effect, had no effects in these assays. Guggulipid (20 g/kg diet) improved glucose tolerance in female Lep(ob)/Lep(ob) mice. Pure commipheric acid, given orally (960 mg/kg body weight, once daily), increased liver weight but did not affect body weight or glucose tolerance. However, the ethyl ester of commipheric acid (150 mg/kg, twice daily) lowered fasting blood glucose and plasma insulin, and plasma triglycerides without affecting food intake or body weight. These results raise the possibility that guggulipid has anti-diabetic activity due partly to commipheric acid's PPARalpha/gamma agonism, but the systemic bioavailability of orally dosed, pure commipheric acid appears poor. Another component may contribute to guggulipid's anti-diabetic and hypocholesterolaemic activity by stimulating LXRalpha.
Cornick
Claire L
CL
Clore Laboratory for Life Sciences, University of Buckingham, MK18 1EG Buckingham, UK.
Strongitharm
Barbara H
BH
Sassano
Gary
G
Rawlins
Christopher
C
Mayes
Andrew E
AE
Joseph
Alison N
AN
O'Dowd
Jacqueline
J
Stocker
Claire
C
Wargent
Ed
E
Cawthorne
Michael A
MA
Brown
A Louise
AL
Arch
Jonathan R S
JR
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D029744:Commiphora; D017931:DNA Primers; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D020738:Leptin / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010936:Plant Extracts / Q000494:pharmacology*; D053149:Plant Gums / Q000494:pharmacology*
D017931:DNA Primers; D007004:Hypoglycemic Agents; D020738:Leptin; D047493:PPAR alpha; D047495:PPAR gamma; D010936:Plant Extracts; D053149:Plant Gums; C018562:guggulu extract